Cellular/Molecular

Wnts are a large family of secreted proteins that regulate cell polarity and migration throughout development, from gastrulation to synaptogenesis. Wnt binds to Frizzled receptors along with different coreceptors, leading to activation of Disheveled. Depending on which coreceptor is involved and whether Disheveled is localized to the membrane, Wnt signaling either leads to accumulation of cytoplasmic β-catenin, which then enters the nucleus and activates transcription of specific genes (the canonical pathway), or it activates Rho GTPases, calcium influx, protein kinase C (PKC), and/or JNK signaling (noncanonical pathways). Expression of Wnts and their downstream effectors persists in adult CNS and is involved in synaptic plasticity. Cerpa et al. report that Wnt-5a regulates NMDA receptor currents in mouse hippocampal slices. Wnt scavengers reduced NMDA currents, whereas exogenous Wnt-5a increased currents, apparently by increasing the proportion of NMDA receptors incorporating the NR2B subunit. The initial increase required calcium influx and PKC, but sustained increase required JNK signaling.

Behavioral/Systems/Cognitive

Cerebral cortex has expanded over the course of hominid evolution, but not uniformly: anterior prefrontal cortex (aPFC), which is involved in problem-solving and complex planning, is especially enlarged in humans, whereas primary visual cortex (V1) has expanded less. The size of these and other brain areas varies greatly across individuals—up to threefold for V1. Most studies of interindividual differences have asked whether variations in the size of an area correlate with variation in performance on tasks associated with that area. Such correlations have been found. Song et al. asked whether expansion of one cortical area correlated with expansion of other areas in the same person. They found the opposite: V1 volume was inversely correlated with the volume of aPFC and of the gray matter of the entire brain. The volume of aPFC was positively correlated with whole-brain volume, however. Thus, the same volume correlations that occur across species also occur across individual humans.

Neurobiology of Disease

Synaptic activity paired with postsynaptic spiking causes dendritic release of brain-derived neurotrophic factor (BDNF). BDNF binds to postsynaptic receptors, leading to activation of Akt. Akt activates the mammalian target of rapamycin (mTOR), which interacts with translational machinery to stimulate local synthesis of glutamate receptors and other proteins that mediate long-term potentiation (LTP). LTP increases the probability that synaptic activity will cause spiking. Thus, BDNF–mTOR pathways form a positive feedback loop. BDNF levels are elevated in Down's syndrome, and Troca-Marín et al. found that it was also elevated in hippocampal neurons from trisomic mice. Furthermore, Akt, mTOR, and translation initiators were hyperactivated, translation of AMPA receptor subunits was elevated, and these potentiated states could not be further potentiated by BDNF. Rapamycin reduced basal activation of mTOR and its targets to wild-type levels, after which BDNF could upregulate these pathways. Which step in the BDNF–mTOR signaling loop was initially disrupted remains unknown, however.